Zwei Formen familiärer Hypercholesterinämie: Unterschiede bei kardiovaskulären Risikofaktoren sowie kardialer und extrakardialer Atherosklerose

Zusammenfassung

Hintergrund und Fragestellung: Monogenetisch vererbte Hypercholesterinämien gehen mit einem frühzeitigen und sehr hohen KHK-Risiko einher. Wir untersuchten, ob bei Patienten mit zwei verschiedenen Formen der genetischen Hypercholesterinämie Unterschiede bezüglich kardialer und extrakardialer Atherosklerose bestehen.

Patienten und Methoden: Die Daten von Patienten mit nachgewiesener genetischer HC, 54 Patienten mit FH (defekter LDL-Rezeptor) und 54 mit FDB (defektes Apolipoprotein B), wurden in Abhängigkeit vom genetischen Defekt und von anderen kardiovaskulären Risikofaktoren retrospektiv verglichen.

Ergebnisse: Gesamt- und LDL-Cholesterin waren bei Männern mit FH am höchsten und signifikant höher als bei Männern mit FDB. 41,8 % der FH-Patienten hatten eine KHK (Durchschnittsalter 41 Jahre), 5,6 % der FDB-Patienten (52 Jahre). Stenosen > 50 % der Arteria carotis interna fanden sich bei 15 % (FH) bzw. 4 % (FDB) der Patienten, eine PAVK bei 3 FH- bzw. 2 FDB-Patienten. Hypertonie und Zigarettenrauchen waren in beiden Gruppen nahezu gleich häufig, das Gewicht der Patienten meist normal (BMI ≤ 25 kg/m²).

Folgerung: Patienten mit erblicher Hypercholesterinämie erleiden frühzeitig kardiovaskuläre Ereignisse. Patienten mit FH scheinen häufiger betroffen zu sein als Patienten mit FDB. Angesichts des hohen Risikos und der frühen Manifestation müssen genetisch determinierte primäre Hypercholesterinämien frühzeitig diagnostiziert und lebenslang behandelt werden, um die Manifestation der Atherosklerose hinauszuzögern.

Abstract

Background and aim: The monogenetic hypercholesterolemias (HC) are associated with a very high risk of premature coronary heart disease (CHD). We sought to assess the influence of the genetic defect and the cardiovascular risk factors on the manifestation of atherosclerotic complications in two forms of genetic HC.

Patients and methods: Data of patients with genetically defined HC (54 LDL-receptor defective familial hypercholesterolemia (FH) and 54 familial defective apolipoprotein B (FDB)) were analysed retrospectively for cardiac and extracardiac atherosclerosis.

Results: Total and LDL-cholesterol were significantly higher in FH men than in FDB men, but not so in women. 41.8 % of FH patients had CHD (mean age 41 years), 5.6 % of FDB (mean age 52 years). Stenoses (> 50 % narrowing) of the internal carotid artery were verified in 15 % of FH and 4 % of FDB patients. Peripheral arterial disease was found in 3 FH and 2 FDB patients. Hypertension and active smoking were allotted almost equally, body weight was normal in most of the patients (BMI ≤ 25 kg/m²).

Conlusion: Patients with genetic HC suffer from early manifestation of cardiac disease. Patients with FH seem to be affected more often than patients with FDB. Early diagnosis and early and lifelong treatment are essential and, according to the literature, lead to a delay of disease manifestation.

Schlüsselwörter

familiäre Hypercholesterinämie - FH - FDB - Mutationen - Atherosklerose

Keywords

FH - FDB - mutations - atherosclerosis

• Literatur

• 1 Austin MA, Hutter CM, Zimmern RL et al. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol 2004; 160: 407-420
• 2 Bertolini S, Pisciotta L, Rabacchi C et al. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis 2013; 227: 342-348
• 3 Bhatnagar D, Morgan J, Siddiq S et al. Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia. BMJ 2000; 321: 1497-1500
• 4 Catapano AL, Reiner Z, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011; 217 () 3-46
• 5 Heigl C. Genetisch charakterisierte familiäre Hypercholesterinämien: Klinische Befunde, Risikoprofil für kardiovaskuläre Komplikationen, insbesondere die koronare Herzkrankheit in einem Münchner Patientenkollektiv. Inaugural-Dissertation aus der Medizinischen Poliklinik Innenstadt des Klinikums der Universität München (Dir. Prof. Dr. D. Schlöndorff) Medizinische Fakultät LMU; 2010
• 6 Hobbs HH, Leitersdorf E, Leffert CC et al. Evidence for a dominant gene that suppresses hypercholesterolemia in a family with defective low density lipoprotein receptors. J Clin Invest 1989; 84: 656-664
• 7 Jansen AC, van Aalst-Cohen ES, Tanck MW et al. The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients. J Intern Med 2004; 256: 482-490
• 8 Keil U, Liese AD, Hense HW et al. Classical risk factors and their impact on incident non-fatal and fatal myocardial infarction and all-cause mortality in southern Germany. Results from the MONICA Augsburg cohort study 1984-1992. Monitoring Trends and Determinants in Cardiovascular Diseases. Eur Heart J 1998; 19: 1197-1207
• 9 Kotseva K, Wood D, De Backer G et al. EUROASPIRE Study Group. Collaborators (152). Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European countries. Lancet 2009; 373 () 929-940
• 10 Leigh SEA, Foster AH, Whittall RA et al. Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet 2008; 72: 485-498
• 11 Lloyd-Jones DM, Leip EP, Larson MG et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation 2006; 113: 791-798
• 12 Miserez A, Keller U. Differences in the phenotypic characteristics of subjects with familial defective apolipoprotein B-100 and familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 1995; 15: 719-729
• 13 Nordestgaard BG, Chapman MJ, Humphries SE et al. for the European Atherosclerosis Society Consensus Panel. Familial Hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society. Eur Heart J 2013; 34: 3478-90a
• 14 Schuster H, Keller C, Wolfram G et al. Ten LDL receptor mutants explain one third of familial hypercholesterolemia in a German sample. Arterioscler Thromb Vasc Biol 1995; 15: 2176-2180
• 15 Schuster H, Rauh G, Müller S et al. Allele-specific and asymmetric polymerase chain reaction amplification in combination: a one step polymerase chain reaction protocol for rapid diagnosis of familial defective apolipoprotein B-100. Anal Biochem 1992; 204: 22-25
• 16 Stamler J, Daviglus ML, Garside DB et al. Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity. JAMA 2000; 284: 311-318
• 17 Storm R. Wahrscheinlichkeitsrechnung, mathematische Statistik und statistische Qualitätskontrolle. 6.. Auflage Leipzig: VEB Fachbuchverlag; 1976
• 18 Tatò F, Keller C, Schuster H et al. Relation of lipoprotein(a) to coronary heart disease and duplexsonographic findings of the carotid arteries in heterozygous familial hypercholesterolemia. Atherosclerosis 1993; 101: 69-77
• 19 Vega GL, Grundy SM. In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. J Clin Invest 1986; 78: 1410-1414
• 20 Versmissen J, Oosterveer DM, Yazdanpanah M et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 2008; 337: a2423
• 21 Weiss N, Binder G, Keller C. Mutations in the low-density-lipoprotein receptor gene in German patients with familial hypercholesterolaemia. J Inherit Metab Dis 2000; 23: 778-790
• 22 Weiss N, Eggersdorfer I, Keller C. Multiplex-PCR based single-strand conformation polymorphism protocol for simultaneous analysis of up to five fragments of the low-density-lipoprotein receptor gene. Biotechniques 1996; 20: 421-429
• 23 Whitfield AJ, Barrett PH, van Bockxmeer FM et al. Lipid disorders and mutations in the Apo B gene. Clin Chem 2004; 50: 1725-1732
• 24 Williams RR, Hunt SC, Schumacher MC et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol 1993; 72: 171-176